This is a competitive renewal application from an inter-institutional group of investigators with long-standing interest in Angelman syndrome (AS), Rett syndrome (RTT), and Prader-Willi syndrome (PWS) to continue a Rare Diseases Clinical Research Center (RDCRC) within the Rare Diseases Clinical Research Network (RDCRN). The Center will focus on these three disorders based on the expectation that the near-term potential for meaningful therapy is strong. The specific aims for AS are 1) to conduct longitudinal assessments on individuals with AS according to genotype, 2) establish genotype-phenotype correlations based on molecular defect type, and 3) to examine the efficacy of existing therapies including developmental interventions with respect to the genotype-phenotype. The specific aims for RS will be 1) to establish phenotype/genotype correlations over a broad spectrum of Rett phenotypes, 2) to perform longitudinal studies on an extensive population of individuals with Rett, and 3) to extend the survival study on a broad spectrum of Rett individuals. Recent results from studies in animal models provide a basis for clinical trials in the next 5 years. The specific aims for PWS are 1) to conduct longitudinal studies according to genotype, 2) to perform natural history studies on non-PWS individuals with early-onset morbid obesity (EMO) and compare them with PWS, and 3) to develop parameters and tool for clnical trials. A pilot project spanning the three disorders will examine the characteristics and patterns of sleep disorders, well-known accompaniments of each (funded by IRSF). The RDCRC will utilize GCRCs in Birmingham, Boston, Gainesville, Houston, Irvine, Kansas City, and Nashville. The Center is expected to function synergistically with the Intellectual and Developmental Disability Center-IDDRC (formerly the MRRC) at UAB. An extensive training program is proposed for stimulating the entry of new investigators into clinical research on rare diseases (funded by IRSF and PWSA). The Center will have active affiliation with the International Rett Syndrome Foundation (IRSF), the Angelman Syndrome Foundation (ASF), and the Prader- Willi Syndrome Association (PWSA). A website for this RDCRC is available at www.circ.uab.edu. This site will be amplified to include a wide range of information for AS, RTT, and PWS.